Bridged bicyclic ferrocene ethers and thioethers

ABSTRACT

THE COMPOUNDS ARE BRIDGED BICYCLIC FERROCENE ETHERS AND THIOETHERS USEFUL AS PESTICIDES, FUNGICIDES, HEMATINIC AGENTS, HYDROCARBON DYES AND FUEL ADDITIVES. COMPOUNDS DISCLOSED INCLUDE 1,1&#39;&#39;-(A,A&#39;&#39;-EPOXY-$-PHENYL-PENTAMETHYLENE)FERROCENE AND 1,1-(A,A&#39;&#39;ITHIA-$-PHENYLPENTAMETHYLENE)FERROCENE.

United States Patent 3,557,143 BRIDGED BICYCLIC FERROCENE ETHERS ANDTHIOETHERS John T. Suh and Claude I. Judd, Mequon, Wis., assignors toColgate-Palmolive Company, New York, N.Y., a corporation of Delaware NoDrawing. Filed Aug. 30, 1967, Ser. No. 664,276 Int. Cl. C07d 7/04,65/05; C07f /02 US. Cl. 260-327 3 Claims ABSTRACT OF THE DISCLOSURE Thecompounds are bridged bicyclic ferrocene ethers and thioethers useful aspesticides, fungicides, hematinic agents, hydrocarbon dyes and fueladditives. Compounds disclosed include1,1'-(a,a-epoxy-'y-phenyl-pentamethylene)ferrocene andl,1'-(11,0:-thia-'y-phenylpentamethylene)ferrocene.

BACKGROUND OF THE INVENTION SUMMARY OF THE INVENTION The presentinvention relates to novel ferrocene derivatives of the formula I Fe inwhich X is oxygen or sulfur, Y and Z are normal ring substituents, R andR are hydrogen, lower alkyl, cycloalkyl, aryl or aralkyl and Ar is anaryl or a heterocyclic group. It also relates to methods of preparingand using the compounds.

DETAILED DESCRIPTION The compounds of the invention have the followingformula in which X is oxygen or sulfur, Y and Z are preferably hydrogenbut may also be a lower alkyl of 1 to 4 carbon atoms 'or a cyclo-loweralkyl of 3 to 7 carbon atoms, R and R are hydrogen, lower alkyl from 1to 8 carbon atoms such as methyl, ethyl, butyl and heXyl, a cycloalkylof 3 to 7 carbon atoms such as cyclopropyl, cyclohexyl and cyclopentyl,cycloalkyl-lower alkyl in which the cycloalkyl has 3 to 7 carbon atomssuch as cyclopentyl ethyl and cyclohexyl methyl, an aryl such as phenylwhich includes nuclear substituted phenyls such as pmethoxyphenyl ando-chlorophenyl, an aralkyl of 7 to 15 carbon atoms especiallyphenyl-lower alkyl which includes benzyl, phenethyl, phenylisopropyl,and phenylbutyl and including nuclear substituted phenyl-lower alkylssuch as p-methoxy benzyl, and Ar is an aryl such as phenyl whichincludes nuclear substituted phenyls such as p-methoxyphenyl,o-chlorophenyl, p-dimethylaminoethoxyphenyl and p-benzyloxyphenyl andheterocyclic groups such as pyridyl, thienyl, furyl, pyrryl and indolyl.

The compounds of the present invention are conveniently prepared byreacting an appropriate 1,1-diacetyl ferrocene with a suitable aromaticor heterocyclic aldehyde in a nonparticipating solvent such asdimethylformamide to form the corresponding l,1-(a,a'-diketo-'y-aryl orheterocyclic-pentamethylene)ferrocene, The diketo derivative can then betreated with sodium borohydride to form the corresponding dihydoxycompound which upon treatment with acetic acid forms the correspondingbicyclic ether, the l,1-(a,a'-epoXy-'y-aryl orheterocyclic-pentamethylene)ferrocene. If desired, the diketo derivativecan be converted directly to the bicyclic ether by treating it firstwith sodium borohydride and then heating the resulting intermediate.

The 1,-1'-(u,a'-thia-' -aryl or heterocyclic-pentamethylene)ferrocenesmay be conveniently prepared by treat ing the corresponding1,1-(u,a'-dihydroxy-'y-aryl or heterocyclic-pentamethylene)ferrocene ina carboxylic acid containing 1 to 4 carbon atoms such as glacial aceticacid to which a catalytic amount of sulfuric acid has been added withhydrogen sulfide gas.

The described processes may be illustrated as follows:

in which all symbols are as previously described and do not interferewith or partake in the reactions.

Representative of the 'aldehydes that may be employed in the describedprocess are:

' Benzaldeh-yde,

Representative of the intermediate and final compounds which may beprepared by the above processes are:

1,1'-[a,ot-diketo-'y-(phenyD-pentamethylene]ferrocene,

1, 1- a,a-dike-to-'y-(o-chlorophenyl)-pentamethy1ene1 ferrocene,

1,1-[a,u-diketo-' -(p-benzyloxyphenyl)pentamethylene]- ferrocene,

1,1-[aux-diketoy-(p-N-diethylaminoethoxyphenyD- pentamethylene]ferrocene,

1,1-[a,ot-diketo-'y-(4"-pyridyl)-pentamethylene]- ferrocene,

l,1 a,a'-diketo-'y-(p-chlorophenyD-pentamethylene] ferrocene,

1,1'-[u,a'-diketo-'y-(2-furyl)-pentamethyleue]ferrocene,

1,1-[a,a-diketo- -(2-thienyl)-pentamethylene]ferrocene,

1, l a,ot'-dlk6tO'y-( 2"-pyrrolyl -pentamethylene] ferrocene,

1,1'-[a,a'-dik6tO-'y-(3 "-indolyl) -pentamethylene] ferrocene,

1, l '-(a, a'-dihydroxy-'y-phenyl-pentamethylene)ferrocene,

1,1-[a,a-dihydroxy-- -(o-chlorophenyl)-pentamethylene]- ferrocene,

1,1'-[a,a-dihydroxy- -(p-benzoyloxyphenyl)-pentamethylene] ferrocene,

1, 1- a,a'-dihydroxy-'y=(p-N-diethylaminoethoXyphenyD- pentamethylene]ferrocene,

1,1-[a,a'-dihydroxy- -(4"-pyridyl)-pentamethylene]- ferrocene,

1, 1- [a,a'-dihydroxy-v-(p-chlorophenyl)-pentamethylene1 ferrocene,

1,1-[a,a-dihydroxy-y-(2"-furyl)-pentamethylene]-ferrocene,

1,1'-[a,a-dihydroxy-'y-(2-thienyl)-pentamethylene]ferrocenel,1-[a:a-dihydroxy-y-(Z"-pyrrolyl)-pentamethylene]- ferrocene,

1,1-[a,a-dihydroxy-'y-(3"-indolyl)-pentamethylene]ferrocene,

1, 1- (a,a-epoxy-'y-phenyl-pentamethylene)ferro cene,

1 1' s y- -(o-chlorophenyl)-pentamethylene]- ferrocene,

1,1-[c m-epoxy-y-(p-benZyloxyphenyD-pentamethylene]- ferrocene,

1,1-[a,u'-epoxy-'y-(p-N-diethylaminoethoxyphenyD-pentamethylene]ferrocene,

1,1-[a,cU-epoxy-y-(4"-pyridyl)-pentamethylene]ferrocene,

1,1'-[a x-epoxy-y-(p-chlorophenyl)-pentamethylene]- ferrocene,

1, 1- a,a-epoxy-y-(2-furyl)-pentamethylene] ferrocene,

1,1-[ ,od-epoxy-v-(2"-thienyl)-pentamethylene]ferrocene,

1,1-[u,a'-epoxy-' -(2-pyrrolyl)-pentamethylene]ferrocene,

1,1'- U-epoXy- -(2"-indoly1-pentamethylene]ferrocene,

1, 1- (a,ot-thia-'y-phenylp entamethylene) ferro cene,

1, 1- [a,a-thia-y-(o-chlorophenyl) -p entamethylene] ferrocene,

1,1'-[a,ot'-thia-'y-(p-benzyloxyphenyl)-pentamethylene]- ferrocene,

1,1'-[a,a'-thia-'y-(p-N-diethylaminoethoxyphenyD-pentamethylene]ferrocene,

1,1-[a,ot'-thia-'y-(2"furyD-pentamthylene]ferrocene,

1,1-[a,a-thia-'y-(2"-thienyl)-pentamethylene]ferrocene,

1,1'-[a,rid-thia-'y-(2"-pyrrolyl)-pentamethylene]ferrocene,

1,1'-[a,a'-thia-y-(Z"-indolyl)-pentamethylene]ferrocene1,1'-[a,a-thia-'y-(4"-pyridyl)-pentamethylene]ferrocene,

and

1, 1- [a,a-thia-'y-(p-chlorophenyl)-pentamethylene] ferrocene.

The ferrocene derivatives of the present invention may be employed aspetroleum product additives, especially antiknock agents, in the mannerdescribed in US. Pat. No. 3,217,091. In addition, the novel ethers andthioethers of the present invention, as well as the dihydroxyintermediates, show promise as hydrocarbon dyes or inks as they aresoluble in most organic solvents and possess distinctive yellow toyellow-orange colors. They may also be used as anti-corrosion agents,pesticides and fungicides.

The ferrocene derivatives of the present invention are also hematinicagents useful for the treatment of iron deficiencies in animals,especially piglets and humans. The compounds1,l'-(a,tad-epoxy-'y-phenyl-pentamethylene)ferrocene and1,1'-(a,a'-thia-'y-phenylpentamethylene)fe'rrocene when evaluated incontrolled studies in rats made anemic by maintenance on a low iron dietwere found in oral doses of 3 mg./kg. of iron to be effective incorrecting the diet-induced iron deficiency anemia.

In the evaluation procedure female rats were admin istered 3 mg. Fe/kg.of the compounds via a stomach tube five days a week for a two-weekperiod. Controls were employed which received the vehicles but no ironcontaining compounds. Hemoglobin determinations were performed predrugand at one and two week intervals, in addition to a determination oneweek after the end of the dosing period. All the animals were maintainedon a low iron diet and sacrificed at the end of the third week. Thehemoglobin determinations demonstrated that the compounds were effectivein preventing anemia in the animals.

When employed as hematinic agents the ferrocene derivatives arepreferably combined with pharmaceutical diluents and formed into dosageforms suitable for ad ministration such as tablets, capsules, syrups,elixirs, solutions, and the like. The oral route of administration ispreferred, but the compounds may be administered parenterally if sodesired.

Pharmaceutical carriers which are either liquid or solid may beemployed. The preferred liquid carrier is water. However, suitableorganic solvents such as propylene glycol may also be employed.Flavoring materials may be included if desired.

Solid pharmaceutical carriers such as starch, sugar and talc can beutilized to form powders. These powders can be used as such or can betableted or used to fill gelatin capsules. Suitable lubricants such asmagnesium stearate, binders such as gelatin, and disintegrating agentssuch as sodium carbonate in combination with citric acid may be employedin the formation of the tablets.

Unit dosage forms such as tablets and capsules may contain any suitablepredetermined amount of one or more of the active ingredients and may beadministered one or more at a time at regular intervals. Such unitdosage forms, however, should generally contain approximately 5 to 500mg. of the ferroeene bicyclic ether.

A typical tablet may have the following composition:

Mg. Ferrocene bicyclic ether or thioether 250 Polyvinylpyrrolidone(pharmaceutical grade) l5 Corn starch 50 Magnesium stearate 3 Thetablets are formed on a inch deep cup punch and the tablets may becoated if desired.

A typical soft gelatin capsule, size 0, may have the followingcomposition:

Ferrocene bicyclic ether or thioether250 mg. Polyethylene glycol 400-0.5cc. (q.s. ad)

A typical oil solution may contain the following ingredients in eachteaspoonful:

Ferrocene bicyclic ether or thioether-250 mg. Preservatives andflavorq.s. Peanut oil-5 ml. (q.s. ad)

A typical aqueous suspension intended for oral administration maycontain the following ingredients in each teaspoonful:

Ferrocene bicyclic ether or thioether250 mg. Sorbitol1,250 cc.

Sodium carboxymethyl cellulose-50 mg. Cellulose (microcrystalline)-500mg. Preservatives and flavorq.s.

Water5 cc. (q.s. ad)

The exact quantity of the composition to be administered, of course,will depend upon many factors including the elemental iron content ofthe compound and the nature and extent of the iron deficiency of thepatient. However, generally speaking, the amount administered in asingle day will be equivalent to about 5 mg. to about 500 mg. ofelemental iron.

The following examples illustrate the preparation of the compounds ofthe invention:

EXAMPLE 1 1, 1'-(11,0!-diketo-'y-phenyl-pentamethylene)ferrocene To asolution of 0.9 g. (0.022 mole) of sodium hydroxide in 20 of water isadded 60 ml. of dimethylformamide and cooled to 1,1'-diacetylferrocene(2.7 g., 0.01 mole) is added in one portion and stirred until all isdissolved. A solution of 7.17 g. (0.011 mole) of benzaldehyde in 15 ml.of dimethylformamide is added in 2 minutes and stirred 1 hour whileallowing the mixture to warm slowly to room temperature. The mixture isthen cooled in an ice bath and the precipitated solids collected, washedwith water, dried and recrystallized from 650 ml. of acetonitrile toyield l,1'-(oc,a'-dik6tO-'yphenyl-pentamethylene)ferrocene in the formof orange light textured needles, M.P. 294 (d.)

Analysis.Calcd. for C H FeO (percent): C, 70.41; H, 5.06; Fe, 15.59.Found (percent): C, 70.20; H, 4.96; Fe, 15.43. 1

EXAMPLE 2 1,1'-(a,a-dihydroxy-*y-phenyl-pentamethylene)ferrocene To adispersion of 10.0 g. (0.028 mole) of 1,1'-(oz,oc'-diketo-y-phenyl-pentamethylene)ferrocene in 400 ml. of isopropanol isadded 4.2 g. (0.11 mole) of sodium borohydride and the mixture refluxedfor 5 hours. The mixture is concentrated to dryness, 150 ml. ether and100 ml. brine added and the mixture stirred for minutes. The organiclayer is separated, dried and concentrated to yield a semi-solid whichis added to a mixture of 400 ml. of isopropanol and 4.2 g. (0.11 mole)of sodium borohydride and refluxed for 16 hours. The solution isconcentrated to dryness, 150 ml. chloroform and 200 ml. brine added andstirred 10 minutes. The organic layer is separated, dried andconcentrated to yield a solid which is recrystallized three times fromethanol and dried in vacuo at 105 to yield1,1-(a,u-dihydroxy-'y-phenylpentamethylene)ferrocene in the form of ayellow-orange crystalline solid, M.P. 185-190".

Analysis.Calcd. for C H FeO (percent): C, 69.61; H, 6.12; Fe, 15.42.Found (percent): C, 69.80; H, 6.31; Fe, 15.19.

EXAMPLE 3 1,1-(a,a'-epoxy-y-phenyl-pentamethylene)ferrocene A mixture of12.1 g. (0.034 mole) of 1,1'-(a,a'-diketo-'y-phenyl-pentamethylene)ferrocene and 5.1 g. (0.135 mole) of sodiumborohydride in 500 ml. of isopropanol is refluxed for 17 hours. Thesolution is cooled and concentrated in vacuo to yield an oil which isheated at 120-125 under high vacuum for 4 hours to yield a solid. Thesolid is chromatographed through aluminum oxide (200 g., 3X 35 cm.)using 1.6 liters of varying proportions of benzene and petroleum etheras an eluent to yield a material which upon recrystallization from 75ml. of ethanol yields 1,1'-(a,a-epoxy-'yphenyl-pentamethylene)ferrocenein the form of gold crystals, M.P. 148 (d.).

Analysis.-Calcd. for C H FeO (percent): C, 69.61; H, 6.12; Fe, 15.42.Found (percent): C, 69.80; H, 6.31; Fe, 15.19.

EXAMPLE 4 1,1'-(a,oU-thia-v-phenyl-pentamethylene)ferrocene To asolution of one drop of concentrated sulfuric acid in 50 ml. of glacialacetic acid saturated with hydrogen sulfide is added 2.0 g. (0.0055mole) of crude 1,1'-(oc,oc'- dihydroxy-v-phenyl pentamethylene)ferrocenedissolved in 30 ml. of benzene in 5 minutes. While passing hydrogensulfide through the solution at a moderate rate, it is stirred at roomtemperature 0.5 hour and heated at for 1 hour. It is cooled andconcentrated in vacuo. The residue is dissolved in 250 ml. ofchloroform, washed with 50 ml. of brine and once with 100 ml. ofsaturated sodium bicarbonate solution, dried and concentrated. Theresidue is chromatographed through aluminum; oxide (100 g., 3X 16 cm.)using 300 m1. of 35% benzene in petroleum ether as an eluent to yield asolid material which is recrystallized from benzene to yield1,1'-(a,a-thia-y-phenyl-pentamethylene)ferrocene in the form of a yellowpowder, M.P. 219221.

Analysis.Calcd. for C H FeS (percent): C, 70.00; H, 5.60; S, 8.90. Found(percent): C, 70.34; H, 5.57; S, 8.85.

We claim:

1. A compound of the formula in which X is sulfur, Y and Z are hydrogen,lower alkyl of 1 to 4 carbon atoms or cycle-lower alkyl of 3 to 7 carbonatoms, R and R are hydrogen, an alkyl of 1 to 8 carbon atoms, cycloalkylof 3 to 7 carbon atoms, cyclo alkyl-lower alkyl in which the cycloalkylhas 3 to 7 carbon atoms, phenyl, methoxyphenyl, chlorophenyl, benzyl,phenethyl, phenylisopropyl, phenylbutyl, and methoxybenzyl and Ar isphenyl, methoxyphenyl, chlorophenyl, benzyloxyphenyl anddimethylaminoethoxyphenyl.

2. A compound of claim 1 in which Y, Z, R and R are hydrogen.

3. A compound of claim 1 in which Y, Z, R and R are hydrogen and Ar isphenyl.

References Cited UNITED STATES PATENTS 3,417,118 12/1968 Schnettler ctal. 260-439 3,382,267 5/1968 Suh 260439 OTHER REFERENCES Fieser et al.:Org. Chem. (Heath, Boston, 1950), pp. 49-50.

HENRY R. JILES, Primary Examiner C. M. SHURKO, Assistant Examiner US.Cl. X.R.

